Vinflunine

Abstract: Purpose The present study sought to identify pretreatment prognostic factors for overall survival (OS) in patients with metastatic transitional cell carcinoma of the urothelial tract (TCCU) who experienced treatment failure with the first-line, platinum-based regimen included in the phase III vinflunine trial. Patients and Methods In total, 370 patients with platinum-refractory TCCU were included in this analysis. Potential prognostic factors were recorded prospectively. Univariate analysis was used to identify clinical and laboratory factors that significantly impact survival. Multivariate analysis was used to identify independent prognostic factors, and bootstrap analysis was performed for internal validation, forming a prognostic model. External validation was performed on the phase II vinflunine study CA183001. Results Multivariate analysis and the internal validation identified Eastern Cooperative Oncology Group performance status (PS) more than 0, hemoglobin level less than 10 g/dL, and the presence...

Abstract: Vinflunine is a new Vinca alkaloid uniquely fluorinated, by the use of superacid chemistry, in a little exploited region of the catharanthine moiety. In vitro investigations have confirmed the mitotic-arresting and tubulin-interacting properties of vinflunine shared by other Vinca alkaloids. However, differences in terms of the inhibitory effects of vinflunine on microtubules dynamics and its tubulin binding affinities have been identified which appear to distinguish it from the other Vinca alkaloids. Vinflunine induced smaller spirals with a shorter relaxation time, effects, which might be associated with reduced neurotoxicity. Studies investigating the in vitro cytotoxicity of vinflunine in combination therapy have revealed a high level of synergy when vinflunine was combined with either cisplatin, mitomycin C, doxorubicin or 5-fluorouracil. Furthermore, although vinflunine appears to participate in P-glycoprotein-mediated drug resistance mechanisms, it has proved only a weak substrate for this protein and a far less potent inducer of resistance than vinorelbine. Vinflunine was identified in preclinical studies as having marked antitumour activity in vivo against a large panel of experimental tumour models, with tumour regressions being recorded in human renal and small cell lung cancer tumour xenografts. Overall its level of activity was superior to that of vinorelbine in many of the experimental models used. Interestingly, an in vivo study using a well vascularised adenocarcinoma of the colon has suggested that vinflunine mediates its antitumour activity at least in part via an antivascular mechanism, even at sub-cytotoxic doses. Therefore, these data provide a favourable preclinical profile for vinflunine, supporting its promising candidacy for clinical development. Phase I evaluations of vinflunine have been completed in Europe and phase II clinical trials are now ongoing.

Abstract: The clinical interest of Vinca alkaloids was clearly identified as early as 1965 and so this class of compounds has been used as anticancer agents for more than 30 years. Today, two natural compounds, vinblastine and vincristine and two semi-synthetic derivatives, vindesine and vinorelbine, have been registered and thus Vinca alkaloids can be considered to represent a chemical class of definite utility in cancer chemotherapy. Today, relatively few groups actively research in the chemistry of Vinca alkaloids. However, using superacidic chemistry, a new family of such compounds was synthesised and vinflunine, a difluorinated derivative, was selected for clinical testing. A consideration of the pharmacological data relating to these new derivatives appears to reveal a lack of any marked correlation between in vitro and in vivo results. Furthermore, structure/activity relationships have failed to assist the chemist in the rational design. Such rational design of new derivatives is limited by the fact that the Vinca binding site(s) on tubulin and the exact mechanism(s) of action of Vinca alkaloids remain unclear. Nevertheless, the preclinical evaluations of the new derivative vinflunine have already suggested that certain in vitro assays, in addition to in vivo experiments, could be proposed to select more rationally newer generation Vincas. Moreover, recent studies have demonstrated that certain newly identified properties, such as antiangiogenic activities, could enlarge the therapeutic usage of natural and semi-synthetic Vinca alkaloids. Thus, Vinca alkaloids remain a drug family with a continuing interest for future anticancer therapy.

Abstract: Summary Background No standard treatment exists for patients with platinum-refractory urothelial cancer. Taxanes and vinflunine are commonly used, but response is less than 20% with no survival benefit. In this phase 2 study, we assessed efficacy and tolerability of nanoparticle albumin-bound (nab) paclitaxel in platinum-refractory urothelial cancer. Methods We did an open-label, single-group, two-stage study at five centres in Canada. We enrolled patients aged at least 18 years with histologically confirmed, locally advanced, or metastatic measurable urothelial cancer, with documented progression on or within 12 months of treatment with one previous platinum-containing regimen. Patients received nab-paclitaxel at 260 mg/m 2 intravenously every 3 weeks. Treatment continued until disease progression or occurrence of unacceptable toxic effects. The primary endpoint was objective tumour response, defined by a complete response (CR) or partial response (PR) according to Response Evaluation Criteria In Solid Tumors (version 1.0) criteria. Tumour response and safety were assessed in all patients who received at least one cycle of nab-paclitaxel. This study is registered with ClinicalTrials.gov, number NCT00683059. Findings We enrolled 48 patients between Oct 16, 2008, and June 23, 2010. Patients received a median of six cycles (range one to 15). 47 patients were evaluable; one (2·1%) had a CR and 12 (25·5%) had PRs, resulting in an overall response of 27·7% (95% CI 17·3–44·4). The most frequently recorded adverse events of any grade were fatigue (38 of 48; 79%), pain (37 of 48; 77%), alopecia (34 of 48; 71%), and neuropathy (30 of 48; 77%). The most frequently recorded adverse events of grade 3 or higher were pain (11 of 48; 23%), fatigue (five of 48; 23%), hypertension (three of 48; 6%), neuropathy (three of 48, 6%), and joint stiffness or pain (two of 48; 4%). Interpretation Nab-paclitaxel was well tolerated in this population of patients with pretreated advanced urothelial cancer with an encouraging tumour response. These results warrant further study of nab-paclitaxel in second-line treatment of urothelial cancer. Funding Abraxis Bioscience, Celgene.